Majority of cancer patients will die of metastases originating from disseminated tumor cells (DTCs), years or even decades after treatment. This suggests that DTCs survive in a dormant, nonproliferative state. However, because the biology of DTCs is poorly understood it is critical to ask basic mechanistic questions to further develop translational approaches. Our goal is to identify these mechanisms by combining powerful In vivo models and novel imaging and nano-device technologies available through this collaboration. This consortium provides unprecedented synergy to study dormancy and address three emphasis areas of this RFA: 1) tumor dormancy, activation of dormant cells and the tumor microenvironment (SAI), and dormancy in response to cancer treatment (SA2); 2) imaging the tumor microenvironment during tumor metastasis, and dormancy (SAI), as well as in response to therapies (SA2) and 3) characterization and functional relevance of the tumor microenvironment extracellular matrix (ECM) and how tumor cells stroma interactions (i.e. niches) establish metastatic cell fate (SA2). We hypothesize that at least two scenarios influence DTC dormancy. Scenario 1: DTCs from invasive cancers activate stress signals in response to a growth-restrictive target organ microenvironment inducing dormancy. Scenario 2: therapy and/or microenvironmental stress conditions (e.g. hypoxia) acfing on primary tumor cells carrying a